γ-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter, is well known for its presence in the central nervous system. But new research reveals that GABA released from peripheral terminals of nociceptors reverses thermal pain hypersensitivity in a mouse model of inflammatory pain
GABA acted on GABAB1 receptors to reverse sensitization of the transient receptor potential vanilloid type 1 channel (TRPV1), with no effect on normal functioning of the channel. Peripheral GABA signaling could be a novel target to reverse TRPV1 sensitization and ease inflammatory pain.
Inflammatory mediators trigger intracellular signaling pathways that sensitize TRPV1 and increase pain. “This means that any sort of strategy to interfere with that sensitization could interfere with hyperalgesia.”
The authors propose a model in which TRPV1 sensitization is kept in check by GABA—which is released in response to TRPV1 activation.
“The notion that nociceptive neurons release various transmitters into their surroundings is not new,” said Caterina, “but the idea of GABA release certainly is.”
TRPV1 blockers developed thus far have produced side effects including hyperthermia and impaired noxious heat sensation, preventing their use in people and bolstering the search for new ways to target channel sensitization for pain relief (see PRF related discussion here).
GABA agonists, too, have documented analgesic properties, but they also produce side effects, because GABA receptors are expressed throughout the central nervous system (see PRF related news story).